A Sulfonic Acid Polyvinyl Pyridinium Ionic Liquid Catalyzes the Multi-Component Synthesis of Spiro-indoline-3,5′-pyrano[2,3-d]-pyrimidines and -Pyrazines

A sulfonated poly-4-vinyl pyridinium (PVPy-IL-B-SO3H) containing an acidic pyridinium/HSO3− ionic liquid moiety was prepared and used as a catalyst for the three-component reaction of malononitrile with 1-alkylindoline-2,3-diones and 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione or methyl 5-hydroxy-1H-pyrazole-3-carboxylate, leading to methyl 6′-amino-5′-cyano-2-oxo-2′H-spiro[indoline-3,4′-pyrano[2,3-c]pyrazole]-3′-carboxylates or -3,4′-pyrano[2,3-d]pyrimidine]-6′-carbonitrile derivatives under ultrasonic irradiation conditions. The solid catalyst allows easy separation, is cheap, produces high yields under mild conditions, and does not require column chromatography for product isolation and purification.


Catalyst Preparation and Characterization
The catalyst PVPy-IL-B-SO3H was prepared as shown in Scheme 3. First, 4-vinylpyridine was reacted with 1,2-oxathiane-2,2-dioxide leading to 4-(4-vinylpyridinium-1-yl)butane-1-sulfonate which represents a type of ionic liquid. Acidification with hydrochloric acid caused the formation of 1-(4-sulfobutyl)-4-vinylpyridinium chloride. This compound was polymerized using azobisisobutyronitrile (AIBN) and the final product was obtained by reaction of the polymer with sulfuric acid (for details, see Materials and Methods). Elemental analysis produced 39.25% C, 5.49% H, 4.04% N, and 17.98% S. Calculated values for complete pyridine-n-Bu-SO3H alkylation and Cl − to − SO3H replacement (C11H17NO7S2, MW = 339.38 g/mol, see Scheme 3) are C, 38.93; H, 5.05; N, 4.13; and S, 18.89%. From the N values, we calculated a 97% match with the ideal catalyst formula shown in Scheme 3; from the S values it was 95%. The barium sulfate test showed that the sample contained a total of 5.06 mmol of SO4 2− ions per gram, which was equal to 5.06 mmol H + /g in the catalyst. The Fourier Transform IR (FT-IR) spectrum ( Figure 1) of the as-prepared PVPy-IL-B-SO3H showed a broad intense band at 2500-3500 cm −1 , which was assigned to C-H stretches of the hydrocarbon groups and O-H stretches of the SO3H group and attached H2O molecules [26], a sharp resonance at 1613 cm −1 assigned to the C=C and C=N stretching vibrations of the pyridyl group, and bands at 1247 (C-N stretching), 1215 (SO2 asymmetric stretching), 1067 (C-N stretching), 1013 (C-C, and C-S stretching), 883 (C-H bending, S=O stretching), and 597 cm −1 (C-S bending). A thermogravimetric analysis (TGA) of PVPy-B-SO 3 H showed two main stages of weight loss ( Figure 2). The first stage occurred from 200 to 400 • C with an approximate weight loss of about 50%, which might be related to the splitting of the sulfonic acid butyl groups. The second stage of weight loss of another 50% from 400 to 600 • C was probably related to the destruction and degradation of the polymer structure. The differential thermal analysis (DTA) showed two major endothermic peaks at 270 • C, probably corresponding to the cleavage of SO 2 or SO 3 and at 475 • C, indicating CO 2 release during polymer degradation ( Figure 2).  A thermogravimetric analysis (TGA) of PVPy-B-SO3H showed two main stages of weight loss ( Figure 2). The first stage occurred from 200 to 400 °C with an approximate weight loss of about 50%, which might be related to the splitting of the sulfonic acid butyl groups. The second stage of weight loss of another 50% from 400 to 600 °C was probably related to the destruction and degradation of the polymer structure. The differential thermal analysis (DTA) showed two major endothermic peaks at 270 °C, probably corresponding to the cleavage of SO2 or SO3 and at 475 °C, indicating CO2 release during polymer degradation ( Figure 2).
A yield of 95% was obtained using a 0.04 g catalyst in EtOH under reflux for 50 min ( Table 1, entry 4). A higher amount of catalyst (0.06 g) and a slightly shorter reaction time (45 min) produced the same result (entry 6). Non-polar solvents such as diethyl ether (Et2O), n-hexane, toluene, ethyl acetate (EtOAc) and CH2Cl2 were unsuitable and produced no conversion, while the polar solvents DMF (23%), CH3CN (48%), and H2O (45%) produced low yields. Reactions without a catalyst produced no conversion (entry 1), and lower T than reflux (78 °C) produced lower yields (entries 2 and 3).
In a previous study, isatin was reacted with malonitrile and 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione using oleic acid as a homogeneous acid catalyst, and the NH (instead of NEt) derivative of 1c was obtained in an 89% yield in 30 min [22]. The best results for the four-component reaction of indoline-2,3-dione and pyrimidine-2,4,6(1H,3H,5H)-trione with methylamine and nitroketene dithioacetals to 7 -(methylamino)-6 -nitrospiro[indoline-3,5pyrano[2,3-d]pyrimidine]-2,2 ,4 (1 H,3 H)-trione similar to 1c (NO instead of CN, MeNH instead of NH 2 on the pyrane, and NH instead of NMe on the pyrimidine) were obtained without any catalyst. The components were heated 7 h in water and a yield of 72% was obtained [4,15]. Mixing EtOH to the water produced essentially the same yield (70%). Shorter reaction times of 24 h were obtained in EtOH under reflux but produced only a 65% yield. Even lower times of 3 h required base catalysts as piperidine or Et 3 N and produced only a 59 and 54% yield, respectively [15]. Using no solvents (neat) and a sulfonated silica catalyst for the above-mentioned product (NH instead of NEt) produced an excellent yield of 91% and a reaction time of 40 min [36]. These results are in line with our finding that EtOH is an ideal solvent for this reaction. Further, this comparison shows that our catalyst shows high activity in conjunction with the ultrasonic conditions. Furthermore, a series of syntheses starting from isatin, malonitrile, and various 1,3-diketones clearly showed the necessity of a catalyst, here citric acid, to come to reasonable reaction times (less than 2 h) and good yields (higher than 90%) [12].
When making an overall comparison over the so-far reported methods for this type of reactions, it first becomes clear that acid catalysts are superior to bases in terms of reaction times [4,7,22], and both are superior to procedures without any added catalyst [4,7,12,15,21,22]. The use of light to initiate such reactions has turned out to be not as efficient as acid-catalyzed reactions. Syntheses comparable to ours required reaction times from 4 to 12 h at ambient temperature and 18 W while light LEDs [13]. Highly efficient recoverable catalysts have been developed [4,7,19,20,[35][36][37][38], including SO 3 H functionalized nanomaterials and polymers [4,7,19,20,35,36], 1-(2-aminoethyl)piperazine modified graphene oxide material [11], and L-proline-melamine polymers [38]. They are generally easier to separate than homogeneous catalysts. Even the simple Lewis acid salts such as CaCl 2 has been successfully used [39]. As in our case, some approaches have also used ultrasound to activate the solid catalysts and substrates [7,24,26,38].
Importantly, in our study we could show that our product 1c (and all other products in this study) can be separated from the PVPy-IL-B-SO 3 H catalyst by simple filtration and the purification required only re-crystallization and not laborious column chromatography as in all previous reports, even including those with easily removable catalysts [4,7,19,20,[35][36][37][38][39]].

Mechanistical Considerations
Mechanistically, we assume that the reaction is initiated by protonation of the 1ethylindoline-2,3-dione at the carbonyl group enabling the nucleophilic attack of the malononitrile (Scheme 4).

Mechanistical Considerations
Mechanistically, we assume that the reaction is initiated by protonation of the 1-ethylindoline-2,3-dione at the carbonyl group enabling the nucleophilic attack of the malononitrile (Scheme 4).

Scheme 4.
Proposed mechanism of the formation of the pyrimidine 1c.
A Knoevenagel-like condensation then leads to the formation of the intermediate 1.
Similar intermediates have previously been isolated and characterized, underpinning our assumption [5,7,13,24]. The reaction continues with the nucleophilic attack of the enolic form of 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione to the intermediate 1 similar to a Michael addition leading to the formation of the intermediate 2 [5,7,18,24]. The protonation of the imine nitrogen in 2 and the formation of an enolic structure in the pyrimidine core provides the conditions for the cyclization reaction, which leads to the product 1c. This proposed mechanism is completely in line with mechanistic studies on similar spirooxindole products [5,7,13,18,24].
We assume that the pyridinium/SO3H − ionic liquid moiety is slightly more acidic than the sulfonic acid chain, but both very probably contribute to the protonation-deprotonation reactions in the catalytic cycle.
Similar intermediates have previously been isolated and characterized, underpinning our assumption [5,7,13,24]. The reaction continues with the nucleophilic attack of the enolic form of 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione to the intermediate 1 similar to a Michael addition leading to the formation of the intermediate 2 [5,7,18,24]. The protonation of the imine nitrogen in 2 and the formation of an enolic structure in the pyrimidine core provides the conditions for the cyclization reaction, which leads to the product 1c. This proposed mechanism is completely in line with mechanistic studies on similar spirooxindole products [5,7,13,18,24].
We assume that the pyridinium/SO 3 H − ionic liquid moiety is slightly more acidic than the sulfonic acid chain, but both very probably contribute to the protonation-deprotonation reactions in the catalytic cycle.
In a comprehensive study similar to ours, substituents were varied on the is phenyl core when synthesizing NPh (pyrazine) derivatives [23]. As in our study, th troduction of substituents ranging from electron-donating CH3 to electron-withdraw Br or NO2 did not alter the yields markedly [23]. The same was found for H, Cl, B NO2 substituted isatins [20]. This study did also not reveal any difference between or NPh derivatives on the pyrazine concerning the yields.
Finally, we studied the synthesis of the pyrazole 1d using a recovered catalyst ( ure 4). In 10 subsequent runs, the yields decreased from 95 to about 90%.  Table 3. In a similar study, Mn 2 O 3 nanoparticles were used as catalysts, and a similar pyrazole with R = H and a CH 3 substituent instead of the ester function was produced in 97% yield [33]. Using the Carbon-SO 3 H catalyst, the yield for this reaction was 90% [20]. The NPh derivative was obtained in 86% using SiO 2 -SO 3 H as catalyst [19].
In a comprehensive study similar to ours, substituents were varied on the isatin phenyl core when synthesizing NPh (pyrazine) derivatives [23]. As in our study, the introduction of substituents ranging from electron-donating CH 3 to electron-withdrawing Br or NO 2 did not alter the yields markedly [23]. The same was found for H, Cl, Br or NO 2 substituted isatins [20]. This study did also not reveal any difference between NH or NPh derivatives on the pyrazine concerning the yields.
Finally, we studied the synthesis of the pyrazole 1d using a recovered catalyst (Figure 4). In 10 subsequent runs, the yields decreased from 95 to about 90%.  In a similar study, Mn2O3 nanoparticles were used as catalysts, and a similar pyrazole with R = H and a CH3 substituent instead of the ester function was produced in 97% yield [33]. Using the Carbon-SO3H catalyst, the yield for this reaction was 90% [20]. The NPh derivative was obtained in 86% using SiO2-SO3H as catalyst [19].
In a comprehensive study similar to ours, substituents were varied on the isatin phenyl core when synthesizing NPh (pyrazine) derivatives [23]. As in our study, the introduction of substituents ranging from electron-donating CH3 to electron-withdrawing Br or NO2 did not alter the yields markedly [23]. The same was found for H, Cl, Br or NO2 substituted isatins [20]. This study did also not reveal any difference between NH or NPh derivatives on the pyrazine concerning the yields.
Finally, we studied the synthesis of the pyrazole 1d using a recovered catalyst (Figure 4). In 10 subsequent runs, the yields decreased from 95 to about 90%.  Table 3.  Table 3.
In future work, we will study the reuse and recycling of the PVPy-IL-B-SO 3 H catalyst in more detail, as well as its biodegradability. 3.1.2. Acidity Measurement Using the Barium Sulfate Test 1 g of the as-prepared catalyst was dispersed in 100 mL of deionized water and combined with a solution of H 2 O 2 (50 mL, 30%) and NaOH (2 g), and the resulting mixture was stirred for 2 h at 50 • C to convert all sulfonic groups to sulfate (SO 4 2− ) ions. Next, the solution was titrated with a solution of BaCl 2 (1 M). The precipitated BaSO 4 was collected, dried and carefully weighed. The amount of sulfate ions accounts for 5.06 mmol/g catalyst. Accordingly, the total H + capacity of the catalyst was 5.06 mmol H + /g.

General Procedure for the Preparation of the Pyrimidines (1-6)c
In typical reaction in a 25 mL flask equipped with a condenser, 0.04 g of PVP IL-B-SO 3 H was added to a mixture of 66.1 mg (1 mmol) malononitrile, 175 mg (1 mmol) 1-ethylindoline-2,3-dione, and 260 mg (1 mmol) 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)trione in 10 mL EtOH under stirring. The mixture was irradiated in an ultrasonic bath at 80 • C for 50 min. The progress of the reaction was monitored by thin-layer chromatography (TLC). After completion, the catalyst was filtered off using a paper filter, washed with acetone and dried. The filtrate was evaporated to dryness and the crude product was purified by recrystallization from EtOH.